In Phase I, lipid-linked Air and lipid-linked ddI were developed and demonstrated to be more efficacious than the unmodified drugs. This grant will continue the development of lipid-linked antiHIV drugs and incorporate these "prodrugs" into microparticles in order to target the prodrugs to the macrophage sanctuary for HIV. The incorporation of prodrugs into microparticles provides a vehicle for delivery of prodrug at a high concentration primarily to phagocytic cells. The microparticles are composed of a biodegradable copolymer, which remains intact sufficiently long to prevent the premature release of antiviral prodrugs prior to their ingestion by macrophages. After the prodrugs are released in the macrophage, the prodrug is activated by the action of esterase enzymes on the ester bond in the prodrug. The Phase II Specific Aims are: I) Develop routes for the economical synthesis of lipid-linked anti-HIV drugs and perform scaled-up synthesis; 2) Determine rates of enzymatic hydrolysis of ester-containing prodrugs; 3) Incorporate prodrugs into biodegradable microparticles; and 4) Using the MAIDS model, determine the therapeutic efficacy of microparticles containing various combinations of lipid-linked reverse transcriptase inhibitor (RTI) and protease inhibitor (PI) drugs. Administration of microparticles containing lipid prodrugs of RTI and PI to patients infected with HIV has the potential advantages listed under "Commercial Applications." PROPOSED COMMERCIAL APPLICATION: 1) Drug reservoirs would be established in both infected and uninfected cells. 2) As shown by Phase I results, the prodrugs would provide a more stable and less toxic concentration of drug in uninfected cells. 3) Adverse reactions to drugs would be reduced because of the targeting of microparticles primarily to macrophages, the longer biological half life of lipid-linked prodrugs, and the sustained release characteristics of the microparticle formulation.